Psoriasis is a common, inflammatory disease of the skin characterized by hyperproliferation of keratinocytes. A variety of antipsoriatic therapies are available, however, due to problems with side effects and variability in clinical response, intense clinical and commercial interest remains in the development of new treatments. In the current studies, we are investigating the antipsoriatic potential of topically administered thiazolidinediones, a novel class of drugs that has been shown to inhibit the proliferation of a variety of cell types including keratinocytes. These drugs have been shown to have antipsoriatic effects when adminstered orally and previous Phase I STTR studies have indicated that they may also be effective when topically administered. In this Phase II application, we are continuing development of an extremely potent thiazolidinedione for topical treatment of psoriasis. We are testing for optimal dose concentrations in state-of-the art animal models of psoriasis and are performing toxicology studies to determine the safety profile with topical administration. In addition, we are exploring the potential of this agent for use in treatment of other inflammatory skin diseases. We are also testing the anti-psoriatic potential of a related non-thiazolidinedione compound that affects multiple pathways known to influence mechanisms underlying psoriasis. Through these efficacy and safety studies, the current Phase II STTR experiments will provide major steps towards attracting financial support and 3rd party agreements for Phase III commercial development of this new therapeutic option in the management of psoriasis. This project is designed to development a new drug for the treatment of psoriasis, a common and often debilitating skin disease that affects 1-2% of the population. A variety of treatments is available for psoriasis but most are associated with side effects that limit their usefulness. The goal of this project is to develop a safe and effective new drug for topical treatment of psoriasis. [unreadable] [unreadable] [unreadable]